In locally advanced tumors, such as brain tumors, surgery may be used for gross excision, but the surgeon cannot eliminate individual tumor cells, microscopic tumor processes, or tumor-associated vasculature from the normal tissue surrounding the tumor excision site. It is often critical to minimize the volume of surrounding tissue that is excised in such operations. For example, normal brain functions may be severely compromised as a result of tissue loss. Thus, in such cases surgery is often accompanied by radiation therapy and/or chemotherapy in an attempt to kill cancerous cells remaining in the surrounding brain tissue. The chemotherapy may be delivered to the residual tumor cells by a localized or systemic route of administration. By limiting the extent of surgical excision, and relying upon the adjunctive treatments to eliminate the residual cancer cells, the function of an organ may be preserved.
Conventional radiation therapy, using ionizing radiation beams (X-rays, gamma rays, or high energy beta particles), while well-established as an anticancer treatment modality, is not curative in the majority of patients with advanced brain tumors.
Glioblastomas are the most common and malignant type of primary brain cancer and glioblastoma always recur after standard treatment consisting of surgery, radiation and chemotherapy. The overall median survival is only approximately 3 months following surgical resection, 8 months with adjuvant external radiotherapy and 14 months with concurrent and adjuvant alkylating chemotherapy using temozolomide (TMZ). Due to their invasive nature, glioblastomas are non-curable by surgery and side effects as well as poor blood-brain-barrier (BBB) penetration are dose-limiting for conventional chemo- and radiotherapy. Sub-lethal doses may favor escape of cancer cells from therapy and cause resistance development.
Being highly chemo- and radioresistant in experimental studies, a subpopulation of the most resilient cancer cells is most likely a very important part of this therapeutic resistance. These cells are often referred to as cancer cells with stem-like properties or cancer stem cells (CSCs). Cancer stem cells have been described in other cancers, such as lung cancer, malignant melanoma and brain tumors. They appear to replenish the pool of cancer cells, to be highly metastatic and particularly resistant against conventional chemo- and radiotherapies. It is suspected that the cancer stem cells may escape primary therapy due to the limited doses that can be applied.
In most tumors, cancer stem cells comprise no more than 1% of the total tumor cell population, and yet these cells are supposedly responsible for maintaining the growth of the entire tumor by virtue of their capacity for self-renewal and extended proliferation. When transplanted into immunocompromized rodents, only the cancer stem cells are tumor initiating. In fact, cancer stem cells can recapitulate the distinctive microscopic architectural patterns characteristic of the original human tumor from which the cells were isolated. Cancer stem cells are believed to proliferate rather slowly, and they represent only a small proportion of the cycling/dividing cells within a tumor (as observed at a given time). Cancer stem cells give rise to a more rapidly proliferating subpopulation of cancer cells, known as transit-amplifying or progenitor cancer cells, which comprise the vast majority of cycling/dividing cells observed in the tumor. The transit-amplifying cancer cells and cancer stem cells differ in multiple ways. Unlike the cancer stem cells, transit-amplifying cancer cells lack the capacity for self-renewal and undergo only a limited number of cell divisions before completely losing their proliferative capability. In contrast to cancer stem cells, transit-amplifying cancer cells cannot efficiently form progressive tumors when transplanted into immuno-compromised rodents. Transit-amplifying cancer cells give rise to yet another subpopulation of cancer cells that cannot divide. These post-mitotic cancer cells comprise the majority of cells in many solid tumors. Thus, solid tumors are comprised of at least three distinct subpopulations of malignant cells, each endowed with a different capacity for cell division and continuing growth. Indeed, the vast majority of cells in most solid tumors cannot support progressive tumor growth or lead to tumor recurrence after an initial remission or response to treatment.
The tumor-shrinking and/or tumor-inhibiting activities of ionizing radiation and currently used anticancer drugs are believed to involve direct effects on the transit-amplifying cancer cells, and in many cases the blood vessels that supply tumors. None of these two major treatment modalities are capable of eradicating locally advanced solid tumors or preventing the recurrence of locally advanced solid tumors without causing severe damage to the tissues in which the cancer originated; and similarly, none of these major treatment modalities is capable of producing long term remissions of most types of locally advanced solid tumors, even when used in combination. Ionizing radiation and currently used drugs usually provide only a short term effect on tumor growth.
Cancer stem cells can therefore be seen as the root of the tumor, and elimination of transit-amplifying and post-mitotic cancer cell subpopulations resembles weed whacking, because it is invariably associated with re-growth of the tumor. The elimination of cancer stem cells therefore appears to be a prerequisite for curing advanced solid tumors. Consequently, there is a need for identifying targeted agents that can selectively kill the cancer stem cells while sparing normal stem cells.
Cancer stem cells have been isolated and characterized in patients with many types of malignancies, including glioblastoma multiforme. Because cancer stem cells are responsible for the maintenance of glioblastoma multiforme tumors, this subpopulation of cells must be eliminated to prevent tumor recurrence following treatment, and to achieve long term survival.
However, eradicating brain cancer stem cells is a great challenge. There are several problems associated with brain cancer treatment. First, it appears that solid tumors, such as glioblastoma multiforme, are much more genetically and metabolically heterogeneous than previously anticipated. Solid tumors, as well as the cancer stem cells that drive their growth, appear to be genetically and metabolically heterogeneous despite a common organ or tissue of origin, and despite very similar appearances under the microscope. This is especially true of malignant gliomas, which arise in the central nervous system. In view of the genetic/metabolic heterogeneity of solid tumors, biochemical targeting (i.e. the search for agents that specifically target the stem cells in each type of tumor) is a daunting challenge. Moreover, brain cancer stem cells and other types of cancer stem cells are inherently resistant to chemotherapeutic agents, in part due to elevated expression of drug efflux transport proteins. Also, brain cancer stem cells are resistant to ionizing radiation due to the preferential induction of DNA damage-response genes that repair DNA damage caused by radiation. For example, glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Finally, brain cancer stem cells are believed to proliferate more slowly than other cell populations within the tumor thereby making them less susceptible to the toxic effects of cell cycle active agents and ionizing radiation. Cancer stem cells are also believed to proliferate/cycle at a slower rate than their immediate progeny, the transit-amplifying cancer cells.
A unique cell killing mechanism that has garnered considerable interest is the release of Auger electrons. These electrons are emitted by radionuclides that decay by electron capture and internal conversion. Auger electrons have energies even lower than the energy of the beta particle emitted by tritium. This effect is amplified, because some Auger emitters release multiple electrons with each nuclear transformation. The low energy of the Auger electrons results in extremely short particle path lengths within tissues, which is highly desirable, because it minimizes collateral damage. One molecular entity incorporating 125Iodine is [125I]-iodouridine-deoxyriboside (125I-UdR), a thymidine analog. 125I-UdR is recognized by DNA polymerases as a normal thymidine metabolite, and thus is incorporated into the chromosomes at times of DNA synthesis. Once incorporated into the DNA, the Auger electrons, with their very short range (often less than 10 nm), have access to the chemical backbone of the DNA duplex. When the 125Iodine atom disintegrates, Auger electrons have the potential to cause severe damage to chromosomes with minimal effect on cells in the immediate vicinity of the target cell.
Despite the recognition that 125I-UdR has a unique cell killing capability, and despite many years of research aimed at exploiting this mechanism of action, including the concept of directly introducing 125I-UdR into tumors (cf. Mairs et al, Br J Cancer. 2000 January; 82(1):74-80), these agents have not been successfully applied to the treatment of cancer. The delivery of 125I-UdR and related agents to solid tumors, using systemic or local administration, has proven to be extremely challenging.
Thus, new therapeutic strategies are called for that are able to eliminate cancer stem cells in treatment of advanced brain tumors.